2,3,4,5-tetrahydro-4,4-dialkyl-1h-1,4-benzodiazepine halides

ABSTRACT

2,3,4,5-Tetrahydro-4,4-dialkyl-1H-1,4-benzodiazepinium halides possess hypotensive activity.

United States Patent [19] Kim 7 [4 1 Sept. 9, 19752,3,4,5-TETRAHYDRO-4,4-DIALKYL-IH-l ,4-

BENZODIAZEPINE HALIDES [75 Inventor: Dong H. Kim, Wayne, Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: Aug. 1,1974

[21] Appl. No.: 493,808

[5 6] References Cited UNITED STATES PATENTS 3,244,698 4/1966 Uskokovicet a1 260/239 BD 3/1969 Fryer et al Carabateas 260/239 BD 260/239 BDOTHER PUBLICATIONS Gatta et al., Chem. Abstracts, Vol. 77, Abstract No.61967g (1972), QDlASl.

Lee, J. Hex. Chem, Vol. 1, pp. 235-238, (1964).

Primary Examiner-Alton D. Rollins Attorney, Agent, or FirmDavid E.Frankhouser 5 ABSTRACT 2,3,4,5-Tetrahydro-4,4-dialkyllH-l ,4-benzodiazepinium halides possess hypotensive activity.

4 Claims, No Drawings 1 2,3,4,5-TETRAHYDRO-4,4-DIALKYL-ll-l-l,4-

BENZODIAZEPINE HALIDES 2,3 ,4,5-Tetrahydro-1H-1,4-benzodiazepine,dihydro chloride, is described by Uskokovic et al., J. Org. Chem., 27,3606 (1962). The l-methyl-4-aryl derivatives thereof are described byCheuk-Man Lee, J. Heterocyclic Chemistry, 1, 236 (1964).

The invention sought to be patented comprises chemical compounds of themolecular structure N G) X6 wherein R and R are, independently, methyl,ethyl, or propyl; R is hydrogen, methyl, ethyl, or propyl; and X is thechlorine, bromine, or iodine anion.

The compounds of the invention are prepared by treating a compound ofthe formula where R and R have the meanings as above-defined, with analkyl halide (RX). The above-described starting compounds can beprepared by reduction of an appropriately substituted 31-1-1,4-benzodiazepine- 2,5(1H,4H)dione with lithium aluminium hydride intetrahydrofuran. [See Uskokovic, J. Org. Chem., 27, 3606 1962).]3H-1,4-Benzodiazepine- 2,5(1H,4H)dione was prepared according to themethods described by Carabateas and Harris, J. Med. Chem., 9, 6 (1966).This method involves the reaction of isatoic anhydride with glycineethyl ether hydrochloride in refluxing dimethyl formamide (DMF). In thepreparations described herein in the Examples, pyridine was used inplace of DMF. This modification improved the yield and simplified theWork up procedure. For example, using pyridine in place of DMF, theyield of 3H-1,4 benzodiazepine-2,5(1H,4H)dione was increased from 20%(as reported by Carabateas) to 64%.31-1-1-Methyl-l,4-benzodiazepine-2,5( lH,4H)-dione was prepared in twosteps. First, N-methylisatoic anhydride was allowed to react withglycine ethyl ester hydrochloride in refluxing pyridine to giveo-(methylamino)hippuric acid ethyl ester. Second, theo-(methylamino)hippuric acid ethyl ester is ring-closed by fusionwithout solvent.

The following examples are illustrative of the methods of making andusing the compounds of the invention:

EXAMPLE I 3H-l ,4-Benzodiazepine-2,5( lH,4H)-Dione A mixture of isatoicanhydride (1 14.1 g), glycine ethyl ester hydrochloride (105 g) andpyridine (450 ml) was heated under reflux for 7 hr., then chilled in acold room overnight. Product was collected on a filter and washed withwater, then with ethanol several times. Yield 73 g, mp. 328330 dec.

EXAMPLE II o-(Methylamino)Hippuric Acid Ethyl Ester A mixture ofN-methylisatoic anhydride (52 g), glycine ethyl ester hydrochloride ((44g) and pyridine (200 ml) was heated under reflux for 3.5 hr. Thepyridine was removed under reduced pressure to give an oil. Treatment ofthe oil with a large amount of water caused separation of solid materialwhich was collected on a filter and washed with water several times togive 61 g of product, mp. 5559. An analytical sample which was obtainedby recrystallization from ether melted at 7274.5.

Analysis for: C H N O Calculated: C, 6l.O0;-H, 6.83; N, 11.86.

Found: C, 60.97; H, 6.96; N, 11.82.

Hydrolysis of o-(methylamino)hippuric acid ethyl ester afforded thecorresponding acid. A mixture of 4.5 g of o-(methylamino)hippuric acidethyl ester, 30 ml of 15% aqueous sodium hydroxide solution and 10 ml ofethanol was heated under reflux for 1 hr. The reaction mixture wascooled and acidified with dilute hydrochloric acid to pH 3. It wasextracted with ether 3 times. The combined ether extract was dried overanhydrous MgSO Removal of ether in vacuo afforded an oil whichsolidified on standing. Recrystallization from ether afforded 1.3g ofo-(methylamino )hippuric acid, mp. 119122.

Analysis for: C H N O Calculated: C, 57.68; H, 5.81; N, 13.46.

Found: C, 57.93; H, 6.00; N, 13.33.

EXAMPLE Ill 3H-1-Methyll ,4-Benzodiazepine-2,5( 1H,4H )-Dione Nine gramsof o-(methylamino)hippuric acid ethyl ester was fused in an Erlenmeyerflask on a flame for 10 min. After cooling to room. temperature, thesolid material was dissolved in 20 ml of CH Cl with warming on a steambath. Addition of 30 ml of anhydrous ether to the CH CI solution, andsubsequent chilling in ice caused separation of a precipitate which wascollected on a filter and washed with ether to give 3.8 g of theproduct, mp. l84186.

EXAMPLE IV 3H-4-Methyl-l ,4-Benzodiazepine-2,5( lH,4H)-Dione A mixtureof isatoic anhydride (33 g), sarcosine methyl ester hydrochloride (28 g)and pyridine ml) was heated under reflux for 5 hr., then allowed to sitovernight at room temperature. The mixture was chilled in ice, and aprecipitate was collected on a filter. The filter residue was washed!with pyridine, water, then with ethanol to give 20 g of the product, mp.2433-2465 EXAMPLE V 2,3 ,4,5-Tetrahydro- 1H- 1 ,4-BenzodiazepinePowdered 3H-l ,4-benzodiazepine-2 ,5 (1H,4H)- dione (19.1 g) was addedin small portions to a slurry of lithium aluminum hydride (11.3 g) intetrahydrofuran (250 ml) at a rate which causes mild reflux. Theresulting mixture was heated under reflux for 7 hr., then allowed to sitovernight. The mixture was treated with l 1 ml of water, 1 l mlv ofaqueous NaOH solution, then with 33 ml of water. The inorganic salt wasremoved by filtration and washed with tetrahydrofuran several times. Thefiltrate and washings were combined, and evaporated under reducedpressure to give an oil which solidified on standing, giving 15.5 g ofproduct, mp. 8893. Recrystallization from ether improved the mp. to9396.

Analysis for: C H N Calculated: C, 72.94; H, 8.16; N, 18.90.

Found: C, 73.40; H, 8.31; N, 18.88.

EXAMPLE VI l Methyl-2,3 ,4,5-Tetrahydro-1H,-1 ,4-Benzodiazepinel-Methyl-2,3 ,4,5-tetrahydro-lH-1 ,4-benzodiazepine was prepared as inExample V from 10.5 g of l-methyl- 3H-1,4-benzodiazepin-2,5(1H,4H)-dioneand 6.3 g lithium aluminum hydride, giving 9.0 g of the product.

EXAMPLE VII 4-Methyl-2,3 ,4,5-Tetrahydrol H- l ,4-Benzodiazepine4-Methyl-2,3,4,5-tetrahydro- 1 H- l ,4-benzodiazepine was prepared as inExample V from 3H-4-methyl-1,4- benzodiazepine-2,5-( lH,4H)-dione g) andlithium aluminum hydride (12 g).

EXAMPLE VIII 2,3 ,4,5-Tetrahydro-4,4-Dimethyl-1H-l ,4- BenzodiazepiniumIodide A. To an ether solution of 2,3,4,5-tetrahydro-lH-l ,4-benzodiazepine (4.5 g) was added dropwise methyl iodide (4.5 g) dilutedwith 10 ml of ether with stirring at room temperature. A reaction tookplace during the addition. The resulting mixture was stirred at roomtemperature for 5 hr. A precipitate was collected on a filter, andwashed with ether, then with ethanol. The filter residue wasrecrystallized from ethanol to give 2.5 g of product, mp. 196198.

Analysis for: C H IN Calculated: C, 43.43; H, 5.64; N, 9.21.

Found: c, 43.64; H, 5.65; N, 9.32.

B. Methyl iodide (0.7 g) diluted with 3 ml of absolute ethanol was addeddropwise to an ethanolic solution (7 ml) of4-methyl-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine (0.8 g). Theresulting mixture was stirred at room temperature for 6 hr. Chilling ofthe reaction mixture caused separation of a precipitate which wascollected on a filter and washed with ethanol several times. The productweighed 0.65 g and melted at 201 203.

EXAMPLE 1x 2,3,4,5-Tetrahydro- 1 ,4,4-Trimethyl- 1 111-1 ,4-

Benzodiazepinium Iodide 2,3 ,4,5-Tetrahydro-l ,4,4-trimethyl-lH-1 ,4-benzodiazepinium iodide was prepared as in Example VIII A from1-methyl-2,3,4,5-tetrahydro-1H-2,4-

diazepine (2.4 g) and methyl iodide (4.2 g) in ether. The crude product(2.0 g) was recrystallized from ethanol, mp. 155-l56.

Analysis for: C H IN Calculated: C, 45.29; H, 6.02; N, 8.81.

Found: C, 45.08; H, 5.97; N, 8.71.

EXAMPLEv X 1 ,4-Diacetyl-2,3,4,5-Tetrahydro-lH-1 ,4- Benzodiazepine To amixture of 2,3,4,5-tetrahydro-lH-l,4- benzodiazepine (18 g) and pyridineml) was added dropwise acetic anhydride (22 g) at room temperature. Theresulting mixture was heated on a steam bath for 1 hr. Removal ofpyridine under reduced pressure afforded an oil which solidified onstanding. Recrystallization from ether with an addition of a small,amount of ethanol gave 28 g of the product, mp. l19l20.

Analysis for: C H N O Calculated: C, 67.22; H, 6.94; N, 12.06.

Found: C, 67.47; H, 7.00; N, 12.07.

EXAMPLE XI 1 ,4-Diethy1-2,3,4,5-Tetrahydro- 1 H- l ,4- Benzodiazepine 1,4-Diacetyl-2,3,4,5 -tetrahydrol H- 1 ,4- benzodiazepine (12 g) wasreduced with lithium aluminum hydride (5.7 g) in THF (200 ml) heatingunder reflux for 5 hr, then worked-up by a standard procedure, giving9.2 g of the product as an oil.

EXAMPLE XII 1,4-Diethyl-2,3,4,5-Tetrahydro-4-Methyl-1H-l ,4-Benzodiazepinium Iodide 1 ,4-Diethyl-2,3,4,5-tetrahydro-4-methyl- 1 H-1,4- benzodiazepinium iodide was prepared as in Example VIII B froml,4-diethyl-2,3,4,5-tetrahydro-1H-l,4- benzodiazepine (5.7 g) and methyliodide (4.3 g) in ether. The product was recrystallized from ethanol,mp. 174176.

Analysis for: C H IN Calculated: C, 48.56; H, 6.70; N, 8.09.

Found: C, 48.19; H, 6.62; N, 8.10.

EXAMPLE XIII A group of at least six rats is rendered hypertensive byapplying a figure-of-eight legature around one kidney and performing acontralateral nephrectomy. Blood pressure will stabilize at ahypertensive level after approximately six weeks. Systolic pressure ismeasured by an indirect technique using a Decker Caudal Plethysmograph.

Each rat is given the test compound by the oral or LP. route. Bloodpressure is read prior to drug administration and at 2 and 24 hoursthereafter. A control group of rats is run with each group of ratstreated with the test compound. The results of the treated group arecompared to the results of the untreated group by statistical analysis.When tested according to the abovedescribed method, the followingcompounds gave a hypertensive effect at an oral dose of mg/kg.:

2,3 ,4,5-Tetra.hydro-4,4-dimethyll H- l ,4-

benzodiazepinium iodide;

2,3,4,5-Tetrahydro- 1 ,4,4-trimethyl-1H-1 ,4-

benzodiazepinium iodide;

6 l ,4-Diethyl-2,3 ,4,5-tetrahydro-4-methyll H- 1 ,4-

benzodiazepinium iodide. wherein R and R are, independently, methyl,ethyl, or what is claimed isl propyl; R is hydrogen, methyl, ethyl, orpropyl; and X A compound of the formula is the chlorine, bromine, oriodine anion.

5 2. A compound as defined in claim 1 which is: 2,3,4,- R R5-Tetrahydro-4,4-dimethyll H- l ,4-benzodiazepinium iodide.

N G 3. A compound as defined in claim 1 which is: 1,4-

x G Diethyl-2,3,4,5-tetrahydro-4-methyl- 1 PL] ,4-

. benzodiazepinium iodide. N 4. A compound as defined in claim 1 whichis: 2,3,4,- l 2 S-Tetrahydro- 1 ,4,4-trimethyl- 1 1-1-1 ,4 Rbenzodiazepinium iodide.

1. A COMPOUND OF THE FORMULA
 2. A compound as defined in claim 1 whichis: 2,3,4,5-Tetrahydro-4,4-dimethyl-1H-1,4-benzodiazepinium iodide.
 3. Acompound as defined in claim 1 which is: 1,4-Diethyl-2,3,4,5-tetrahydro-4-methyl-1H-1,4-benzodiazepinium iodide.
 4. A compound asdefined in claim 1 which is:2,3,4,5-Tetrahydro-1,4,4-trimethyl-1H-1,4-benzodiazepinium iodide.